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Introduction to ISPE GUIDE:SCIENCE AND RISK-BASED APPROACH FOR THE

DELIVERY OF FACILITIES, SYSTEMS, AND EQUIPMENT

&Overview of Amgen’s CQP

Commissioning and QualificationProgram

Steve Wisniewski Principal Compliance Consultant, CAI

Past Chairman ISPE C&Q COP

May 1-3, 2012

Javits Center

New York, NY

Agenda

– Introduction and Overview of ISPE GUIDE: Science and Risk-

Based Approach for the Delivery of Facility Systems and

Equipment (FSE)

– Overview of Amgen’s CQP Commissioning and Qualification

Program

– Questions ??

What is a Science and Risk Based Approach (RBA)?

A paradigm shift is occurring in the global pharmaceutical industry. The pharmaceutical industry, in conjunction with ISPE is applying an all-encompassing approach to qualification and toward using focused methodologies to assess the scope of qualification.

A science and risk based approach to Qualification of applicable systems and facilities consists of:• The identification and control of risks to product quality• Formality and documentation commensurate with risk• The use of Good Engineering Practices (GEP) to verify installation and operation of systems• Verification that system performance meets product and process user requirements

Think about it:If everything is critical, then nothing is.

Qualification –A Broken Process

• IQ/OQ had become more intensive than PQ.• Organizations refused to leverage commissioning• Automated systems and the controlled equipment

were qualified separately and inefficiently• Deviations for trivial items diluted Q-unit attention• “Change-is-bad” attitudes driven by cost/time

In the Beginning…

A number of seminal documents established the principles of a RBA:

• ISPE Baseline Guide 5 (2001)• “Pharmaceutical cGMPs for the 21st

Century – A Risk Based Approach” – FDA (2004)• ICH Q8 Pharmaceutical Development (2008)• ICH Q9 Quality Risk Management (2006)

• ISPE White Paper – “Risk Based Qualification for the 21st Century” (2005)

• ASTM E 2500 (2007)

10 Principles for Risk-Based Qualification

1. Focus on that which affects product quality

2. Process User Requirements key to acceptability (IQ/OQ subordinate to PQ)

3. Risk assessments and process knowledge used to identify critical elements4. Only critical features/functions to be qualified

5. All activities must contribute value

6. Risk-based asset delivery – not “cookbook” requirements7. Value-added documents based on technical merit

8. Use of supplier documentation

9. Test planning (and one-time testing)10. Foster innovation – all change is not bad

ISPE White Paper “Risk Based Qualification for the 21st Century”March 2005

BG 5Guidance

New Risk-based Approach

ProcessValidation

Engineering Change Management

QA Change Control

IQ & OQ

CommissioningEnhanced Design Review

Design Development

PQ

ProcessValidation

Engineering Change Management QA ChangeControl

Performance Testing

Verification TestingDesign Review

Design Development

PT

Scope of BG 5 vs. FSE GUIDE

Qualified as SuitableFor Intended UseBasis for Suitability:

Process Requirements,Risk Control

FAT Verification Work

SAT Verification Work

Commissioning Verification Work

Figure 2 from “Solving the Terminology Conundrum”Pharmaceutical Engineering, July/August 2008

Qualification –“Traditional” vs. RBA

Traditional Approach• (Product) User Requirements not

Formally Documented• Protocols Developed from

“Templates”• IQ/OQ Protocols “Preapproved”• Commissioning not Leveraged• Engineering and “Validation”

Personnel Often Distinct• Emphasis on Documents – Not

System Performance

RBA Based on ASTM E 2500 • Process Requirements Documented,

Approved

• Risk Assessments Determine Critical Aspects of Design

• Engineering Testing (“Commissioning”) Verification

• All Documents with Technical Merit Used as Evidence of Fitness for Use

• Emphasis on Meeting Process Requirements

Eyes on the Prize

Actual photo of an Abbott Laboratories risk based revalidation paperwork for a legacy control system (on right) vs. previous revalidation “testing everything”

Time & $$$to

Focus on CriticalQuality Issues

FSE- Rationale for the New ISPE GUIDE

Presents a structured lifecycle approach to the delivery of facilities, systems and equipment which support these regulatory initiatives

Designed to improve the way in which the industry delivers regulated manufacturing capacity

– Improve the ability to meet documented process requirements

– Control risks within the manufacturing process

– Produce high quality products which consistently meet product user requirements.

The GUIDE describes the Principles required when applying a science and risk based program.

Structure of FSE GUIDE

Risk Management

Design Review

Change Management

Process Knowledge

Regulatory

Company Quality

Product Knowledge

RequirementsSpecification and Design

VerificationAcceptance and Release

Good Engineering Practice

Reference: Figure 1: ASTM E2500-07, pg 3

FSE GUIDE Overview

Chapters Titles1 Introduction 2 Overview Of The Lifecycle3 Requirements4 Specification & Design5 Verification, Acceptance and Release6 Continual Improvement7 Quality Risk Management8 Good Engineering Practice9 Design Review10 Change Management11-15 Appendices16 Appendix 6 Glossary and Acronyms17 Appendix 7 References

Note : Automation dealt with throughout each chapter

Introduction

This Guide is a key part of the validation life cycle approach to quality assurance to ensure the manufacture of safe and effective products.

The Guide is designed to improve the way in which industry delivers regulated manufacturing capacity:

– to documented process requirements – control risks within the manufacturing process– produce high quality products– consistently meeting product and process requirements

Background

• The successful delivery of manufacturing facilities (including small, large, new, expansion, or renovation type projects) regulated by various authorities, poses significant challenges to manufacturers, engineering professionals, and equipment suppliers.

• These facilities are required to meet all applicable GxP regulations, and to comply with all other relevant local and international governing codes, laws, and regulations.

• This Guide has been published in support of the principles provided in these publications and to provide specific implementation guidance on meeting the expectations of global regulators as embodied in the ICH documents, as applied to the design and delivery of regulated facilities

Relationship of this Guide to InternationalGMP Regs and ICH Guidance Docs

US GMPs EU GMPs Japan GMPs

ICH 08, 09, 10Guidance

ThisGuide

How to perform key elements of Science and Risk-based approach and determine ‘Suitability for Intended Use’.

Scope

– Planning, specification, design, and delivery of facilities/utilities/equipment and associated automation (harmonized) with GAMP 5

– All pharmaceutical manufacturing– Addresses the verification (or

qualification) portion of the validation life cycle on which process validation is built

– New commercial manufacturing and modification to existing regulated mfg facilities

Purpose

• Objective is to facilitate the translation of the scientific product and process knowledge into a documented specification, design, and verification of equipment/systems/utilities which are fit for intended use, and minimize risk to patient safety and product quality

• Approach is built on science based quality risk management, and concepts of Quality by Design

Benefits

Encourage the industry and individual organizations to reassess the terminology, practices, and roles and responsibilities involved in delivering new manufacturing capacity to focus on the criteria required to establish suitability for intended use

Key Concepts

Science Based Quality Risk Management– Describes the importance of a QRM program– Documented risk assessments focused on risk to patient– Focus on identifying , assessing and controlling risk

Product and Process Understanding– Resulting from scientific investigation– Enhanced continually during ongoing operations– Begins with knowing the product CQAs and associated CPPs (ICH Q8R2)

Focus on Achieving Fitness for Intended Use

– Verification activities focused on confirming that CAs of equipment/systems and associated meet acceptance criteria

– Verification inspections and tests are not limited to CAs

Key Concepts (cont.)

Flexible Approaches to Specification and Verification

– Several approaches to structure the documents, inspections, and testing activities

– Demonstration of fit for intended use and sufficient to meet regulatory expectations

Clarification of Roles and Responsibilities

– The roles of Quality Unit and SME are described in the context of the scope of activities covered by this Guide. Subject Matter Experts (SMEs) are defined as those individuals with specific expertise in a particular area or field

– The Quality Unit has a key role within the quality management system governing facilities, systems, and equipment. In addition to acting as a Subject Matter Expert (SME), the Quality Unit is responsible foroverseeing quality and compliance

Role of the Quality Unit

A key focus of the Quality Unit is identifying and approving those aspects that are required to manufacture a quality product, and to ensure that appropriate procedures are followed to ensure that risks to the patient in the manufacturing systems are adequately controlled

The QRM approach recognizes that the GxP regulations provide theQuality Unit with the responsibility for ensuring controls to assure drug product quality

The Risk-Based Verification Process

Verification – ASTM E2500-07

• It is a life-cycle approach – not a check at the end of the process

• It is based on the process and product knowledge, regulatory, and quality standards

• Verification approach must be documented – Verification Plan(s) (approved by quality unit)

• Acceptance criteria must be established• Documented confirmation that the equipment/system is

fit for intended use• Acceptance and release must be documented (approved

by the quality unit)

Overview of Amgen’s CQP Commissioning and Qualification

Program

Special Thanks to :Ronald Brunelle - Quality Assurance DirectorAmgen, Inc.rbrunell@amgen.com

Why do this

Goal

– Simplify Validation

– Better, Cheaper, Faster

Industry Guidance Utilized

– ASTM E2500

– ICH

Agenda

• Introducing Change

• Highlights of the Program

• Lessons Learned and Next Steps

Introducing Change

From Impact Assessments to System Boundaries

• C&Q impact assessments time consuming

• Impact assessment giving inconsistent results across sites

• Component and system impact assessments not helpful in the risk based ASTM 2500 model

Boundary Diagrams

• Boundary diagrams were created for all systems in Amgen

• Allowed a consistent manner for systems and component assessments

• No need to perform the C&Q impact assessment process

• Set the stage for Risk Based approach to qualification

Change from Impact categorization to “Levels” – Mindset Change

• Level 1- Equipment assets within a system where operation or maintenance activities can affect the critical quality attributes, the critical aspects, or the critical process parameters of the product the system delivers.

• Level 2 - Equipment assets within a system where operation or maintenance activities can have an adverse business impact.

• Level 3 - Equipment assets not included in the definitions of level 1 or 2.

Highlights of The Program

The ASTM 2500 Standard

• A science and “risk-based”approach to assure that GMP equipment & systems are:

– Fit for use– Perform satisfactorily

• Amgen interpretation and application of:

– ASTM-2500– ICH Q9– EU Vol. 4 Annex 15– FDA Process Validation

Guidance– ISPE Guide: SCIENCE AND

RISK-BASED APPROACH FOR THE DELIVERY OF FACILITIES, SYSTEMS, AND EQUIPMENT

35

Amgen Document Hierarchyplays key role in change

Quality

Manual

Procedures

GMP

Operating

Standards

Records

Specifications

GMP Quality

Policy

Quality

Manual

Procedures

GMP

Operating

Standards

Records

Specifications

GMP Quality

Policy

Policy:Governing principle/position that mandates or restricts action.

Standard:Operational principles that are typically translated into other required / controlled documents (SOPs) for how to / execution information

Procedure:Instructions for performing tasks, activities or practices that includes the identification of roles and responsibilities.

Commercial Operating Standard forValidation of Level 1 Systems

Site Validation SOPs

Quality Risk Assessment

Automation SOP

GEP SOPs

Commercial Operating Standard for Facility

Design

Using the Document Hierarchy

Integration of Engineering and Quality can be achieved through Document Hierarchy

GEP Framework – 5 SOPs

Engineering Quality

Systems

GEP Framework

Commissioning Planning and

Execution

Sample Summary Reports

Sample Commissioning Plan / template

Sample Commissioning Specifications

Facility commissioning sample report

HAVC System commissioning sample report

Pipe System commissioning sample report

Process Equipment

and Automation guidance

BMA/BAS System

Commissioning sample

report

Security System

Commissioning

Validation, Qualification, and Commissioning Processes

Process

Validation

Implement

for UseCommissioning

IQ

Design

Qualification

Qualification

Validation

Decomm -

issioning

Cleaning

Validation

SIP / PQ

Performance

Monitoring

Change

Control

OQ

Commissioning

Installation

Inspection and

Testing

Development

and Operational

Testing

User

Requirements

Risk

Assessment

I OQ

Verification: Activities within any of these processes

Requirements

Build / Construct

Verification

Accept and Release

Quality

Oversig

ht

Risk assessment controls

confirmed

Strategy scope and acceptance criteria for risk

controls

Risk assessment controls identified

Approvals of program

standards, GEPs

SOPs

Qualification Process and Quality Oversight

Qualification

Specifications and Design

Quality Oversight model at full maturity of the Engineering, Automation and Quality processes

Receipt Verification &InstallationVerification

Design TestBuildPlan

PerformanceTesting / PQ

Quality RiskAssessments

Validation Plan

QualificationSummary Report

CommissioningPlan

Commissioning Tests - Automation checkout, Performancetests, SAT

User Requirements

Design Reviews

Quality ApprovalQuality Review

DevelopmentTesting

FAT

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Amgen Relational Modelfor Qualification

User

Requirements

Design

Review

System

SpecificationsCommissioning

/ Testing

Performance

Qualification

Qualification

report

Vendor

Assessment

Vendor Documents

Good Engineering

Practices

Change

Management

Risk

Assessment

SME’s

Process

Product

System

Regulatory

Quality

Vendors

Feed into ongoing

maintenance

management

systems

Traceability

Lessons Learned - Wins

• One site inspection by agency - the process not challenged

• Resulted in focus of Quality on critical aspects

• Different groups understand and appreciate roles and interactions more clearly

• Faster implementations and more robust systems have been recognized

• System based vs. component based thinking

Lessons Learned - Challenges

• Expectations around documentation practices

• GEPs not well established and understood

• Comfort zones are challenged and resistance varies

• Use escalation process for resistance

Maturing the Process

• Engineering is intensifying their practices and delivery models to provide more robust systems

• Alignment of procedures and practices between groups (Engineering, Automation, Validation)

• Understanding and accountability of SME Role

• Legacy systems applicability

• Intensify training for risk assessments

• Individual site assessments to ensure maturity progression

Benefits Beyond Large Capital Projects

Additional Value• Change Control

Assessments• Failure Event Impact

Assessments• Preventive

Maintenance• Others?

AdditionalBenefits

Adopted Practices

Project Scope

47

Questions

Thank You!

Steve WisniewskiPrincipal Compliance Consultant,

Commissioning Agents Inc.585.704.7585

Steve.Wisniewski@CAgents.com